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The Varicellovirus-Encoded TAP Inhibitor UL49.5 Regulates the Presentation of CTL Epitopes by Qa-1^b1

Thorbald van Hall^2,*, Sandra Laban^*, Danijela Koppers-Lalic^3,, Joachim Koch, Calin Precup^*, Patrick Asmawidjaja^*, Rienk Offringa^* and Emmanuel J. H. J. Wiertz

^* Department of Immunohematology and Blood Transfusion and Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands; and Institute of Biochemistry, Biocenter, Johann Wolfgang Goethe-University, Frankfurt, Germany

Impairment of MHC class I Ag processing is a commonly observed mechanism that allows viruses and tumors to escape immune destruction by CTL. The peptide transporter TAP that is responsible for the delivery of MHC class I-binding peptides into the endoplasmic reticulum is a pivotal target of viral-immune evasion molecules, and expression of this transporter is frequently lost in advanced cancers. We recently described a novel population of CTL that intriguingly exhibits reactivity against such tumor-immune escape variants and that recognizes self-peptides emerging at the cell surface due to defects in the processing machinery. Investigations of this new type of CTL epitopes are hampered by the lack of an efficient inhibitor for peptide transport in mouse cells. In this article, we demonstrate that the varicellovirus protein UL49.5, in contrast to ICP47 and US6, strongly impairs the activity of the mouse transporter and mediates degradation of mouse TAP1 and TAP2. Inhibition of TAP was witnessed by a strong reduction of surface MHC class I display and a decrease in recognition of conventional tumor-specific CTL. Analysis of CTL reactivity through the nonclassical molecule Qa-1^b revealed that the presentation of the predominant leader peptide was inhibited. Interestingly, expression of UL49.5 in processing competent tumor cells induced the presentation of the new category of peptides. Our data show that the varicellovirus UL49.5 protein is a universal TAP inhibitor that can be exploited for preclinical studies on CTL-based immune intervention.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project was financially supported by the Dutch Cancer Society (Grant UL2002-2709 to T.v.H. and S.L.), the Socrates European Student Exchange Program (to C.P.), and the Dutch Diabetes Research Foundation (to D.K.L).

² Address correspondence and reprint requests to Dr. Thorbald van Hall, Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands. E-mail address: T.van_Hall{at}lumc.nl

³ Current address: Department of Pathology, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, U.K.

⁴ Abbreviations used in this paper: ER, endoplasmic reticulum; TEIPP, T cell epitopes associated with impaired peptide processing; BHV1, bovine herpesvirus 1; MCA, 3-methylcholanthrene; AP, alkaline phosphatase.

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